EP0539806B1 - Thiadiazinones et médicaments les contenant, ayant en particulier une activité inotrope positive et vasodilatatrice - Google Patents

Thiadiazinones et médicaments les contenant, ayant en particulier une activité inotrope positive et vasodilatatrice Download PDF

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Publication number
EP0539806B1
EP0539806B1 EP92117675A EP92117675A EP0539806B1 EP 0539806 B1 EP0539806 B1 EP 0539806B1 EP 92117675 A EP92117675 A EP 92117675A EP 92117675 A EP92117675 A EP 92117675A EP 0539806 B1 EP0539806 B1 EP 0539806B1
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EP
European Patent Office
Prior art keywords
phenyl
methoxy
formula
dihydro
thiadiazin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP92117675A
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German (de)
English (en)
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EP0539806A1 (fr
Inventor
Rochus Dr. Jonas
Joachim Dr. Leibrock
Hans-Jochen Dr. Schliep
Christoph Dr. Seyfried
Michael Dr. Wolf
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Merck Patent GmbH
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Merck Patent GmbH
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications

Definitions

  • Structurally similar thiadiazinones are known from EP-A-0 080 296.
  • the compounds of the prior art like the compounds claimed here, have a phenyl radical in the 5-position which can have one to four further substituents, which can be, for example, F, Cl, Br, CF3 or methoxy.
  • Position 6 of the already known thiadiazinones is predominantly unsubstituted.
  • the invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the compounds of the formula I have valuable pharmacological properties with good tolerability. In particular, they show an effect on heart strength (positive inotropic effectiveness); Furthermore, the substances have a vasodilating effect and therefore promote blood circulation.
  • the vasodilating and cardiac effects can e.g. on anesthetized or awake dogs, cats, monkeys or mini-pigs, which have a positive inotropic effect even on isolated heart preparations (e.g. atrium, papillary muscle or perfused whole heart) of rats, guinea pigs, cats or dogs, e.g. according to methods as described in drug research, Volume 31 (I) No. 1a (1981), pages 141 to 170, or by Schliep et al. in the 9th International Congress of Pharmacol., London, Abstracts of papers 9P.
  • the compounds can also be used to treat asthmatic diseases.
  • the anti-asthmatic effect can be determined, for example, by the method of T. Olsson, Acta Allergologica 26 , 438-447 (1971).
  • the compounds also have a cerebroprotective effect, can be used to treat memory disorders and have antidepressant and anti-inflammatory properties.
  • the compounds can therefore be used as active pharmaceutical ingredients in human and veterinary medicine. Furthermore, they can be used as intermediates for the production of further active pharmaceutical ingredients.
  • radicals R1 to R4, R5, A, X and Z and the parameters m and n have the meanings given in the formulas I, II and III, unless expressly stated otherwise.
  • alkyl is preferably unbranched, preferably has 1, 2, 3 or 4 carbon atoms and is preferably methyl, more preferably ethyl or propyl, further preferably isopropyl, butyl, isobutyl, sec-butyl, tert.- Butyl, but also for n-pentyl or isopentyl.
  • Alkoxy is preferably unbranched, preferably has 1, 2 or 3 carbon atoms and is preferably methoxy, more preferably ethoxy or propoxy, furthermore e.g. for isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy or isopentoxy.
  • radicals R1, R2, R3 and R4 have the following preferred meanings: R1 H; R2 is methyl or ethyl; R3 methoxy and R4 difluoromethoxy. If the radicals R3 and / or R4 are different from H, they are preferably in the 3- or 4-position of the phenyl ring.
  • the radical X is preferably F.
  • n are preferably 1, 2 or 3, where n can furthermore preferably be 4, 5, 6 or 7.
  • the compounds of the formula I are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart), under reaction conditions who are known and suitable for the implementations mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
  • R1, R2, R3 and R4 have the meanings given, while Z is preferably Cl or Br.
  • X is a reactive esterified OH group means, this is preferably alkylsulfonyloxy with 1-6 C atoms, for example methanesulfonyloxy or arylsulfonyloxy with 6-10 C atoms, for example benzene-, p-toluene- or 1- or 2-naphthalenesulfonyloxy.
  • R5 preferably represents methyl or ethyl, but also Na, K or ammonium.
  • the starting materials can also be formed in situ in such a way that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • ketones of formula II are accessible, for example, by Friedel-Crafts synthesis from the corresponding phenyl derivatives with compounds of the formula Y-CO-CR1R2-Z, where Y is Cl or Br.
  • Suitable solvents are, for example, hydrocarbons such as benzene, toluene, xylenes or mesitylene; halogenated hydrocarbons such as dichloromethane, trichlorethylene or chlorobenzene; Alcohols such as methanol, ethanol or isopropanol; Glycols and glycol ethers such as ethylene glycol, diethylene glycol, 2-methoxyethanol; Nitriles such as acetonitrile; Ethers such as tetrahydrofuran or dioxane; Amides such as dimethylformamide (DMF); Sulfoxides such as dimethyl sulfoxide. Mixtures of these solvents are also suitable.
  • hydrocarbons such as benzene, toluene, xylenes or mesitylene
  • halogenated hydrocarbons such as dichloromethane, trichlorethylene or chlorobenzene
  • Alcohols such as methanol, ethanol or isopropanol
  • Compounds of the formula I can contain one or more centers of asymmetry. In this case, they are usually in racemic form. Racemates obtained can be separated mechanically or chemically into their optical antipodes by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent.
  • optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.
  • the invention further relates to the use of the compounds of the formula I and their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route.
  • they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more further active ingredients.
  • the invention further relates to agents, in particular pharmaceutical preparations, containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
  • Tablets, dragees, capsules, syrups, juices or drops are used in particular for oral use, and those for rectal use
  • Application suppositories for parenteral application solutions, preferably oily or aqueous solutions, further suspensions, emulsions or implants, for topical application ointments, creams or powders.
  • the new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colors, flavors and / or flavorings. If desired, they can also contain one or more further active ingredients, for example one or more vitamins.
  • the compounds of the formula I can be used in combating diseases, in particular heart failure, and in the therapeutic treatment of the human or animal body.
  • the substances according to the invention are generally administered in analogy to known positively inotropically active substances such as amrinone, preferably in doses between about 1 and 100 mg, in particular between 2 and 20 mg per dosage unit.
  • the daily dosage is preferably between about 0.02 and 2 mg / kg body weight.
  • the specific dose for each particular patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the Elimination rate, drug combination and severity of the disease to which the therapy applies. Oral application is preferred.
  • the compounds of the formula I are distinguished by an improved therapeutic breadth and peripheral relief.
  • customary workup means: If necessary, water or dilute sodium hydroxide solution is added, the mixture is extracted with an organic solvent such as ethyl acetate, chloroform or dichloromethane, the mixture is separated off, the organic phase is dried over sodium sulfate, filtered, evaporated and purified by chromatography and / or crystallization.
  • organic solvent such as ethyl acetate, chloroform or dichloromethane
  • a mixture of 1 kg of 5- (3-methoxy-4-difluoromethoxy-phenyl) -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 10 kg of lactose, 6 kg of microcrystalline cellulose, 6 kg of potato starch, 1 kg of polyvinylpyrrolidone, 0.8 kg of talc and 0.1 kg of magnesium stearate are pressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
  • Example B coated tablets
  • Example A Analogously to Example A, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • a solution of 1 kg of 5- (3-methoxy-4-difluoromethoxy-phenyl) -3,6-dihydro-1,3,4-thiadiazin-2-one in 30 l of 1,2-propanediol is sterile filtered, in ampoules filled, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 2 mg of active ingredient.
  • tablets, coated tablets, capsules and ampoules which contain one or more of the other active compounds of the formula I and / or their physiologically acceptable acid addition salts.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Pulmonology (AREA)
  • Psychiatry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Rheumatology (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (6)

  1. Dérivés de thiadiazinones de formule I
    Figure imgb0011
     où
    R¹ et R² représentent, indépendamment l'un de l'autre, H ou A,
    R³ H, OA ou O-CmH2m+1-nXn,
    R⁴ -O-CmH2m+1-nXn,
    X F ou Cl,
    A un alkyle ayant 1 à 6 atomes de C,
    m est égal à 1, 2, 3, 4, 5 ou 6 et
    n est égal à 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ou 13,
    ainsi que leurs sels.
  2. a) La 5-(3-méthoxy-4-difluorométhoxyphényl)-6-éthyl-3,6-dihydro-1,3,4-thiadiazin-2-one ;
    b) La 5-(3-méthoxy-4-difluorométhoxyphényl)-3,6-dihydro-1,3,4-thiadiazin-2-one .
  3. Procédé pour la préparation des thiadiazinones de formule 1 selon la revendication 1, ainsi que de leurs sels, caractérisé en ce que l'on fait réagir un composé de formule II
    Figure imgb0012
     où R¹, R², R³ et R⁴ ont les significations qui ont été indiquées et
    Z représente Br, Cl, I ou un groupe 0H estérifié réactif,
    avec un composé de formule III



            H₂N-NH-CS-0R⁵   III



    où
    R⁵ représente A, l'ammonium, Na ou K,
    et A a la signification qui a été indiquée,
    et/ou en ce que l'on fait éventuellement réagir un composé correspondant à la formule I, mais qui à la place de R³ et/ou de R⁴ contient un ou deux groupes 0H libres, avec un composé de formule R³-Z ou R⁴-Z où R³, R⁴ et Z ont les significations qui ont été indiquées et/ou en ce que l'on transforme une base de formule I, par traitement avec un acide, en l'un de ses sels.
  4. Procédé pour la préparation de compositions pharmaceutiques, caractérisé en ce que l'on met sous une forme de dosage appropriée un composé de formule I selon la revendication 1 et/ou l'un de ses sels physiologiquement acceptables, associé à au moins un support ou adjuvant , solide, liquide ou semi-liquide .
  5. Composition pharmaceutique, caractérisée en ce qu'elle contient au moins un composé de formule I selon la revendication 1 et/ou l'un de ses sels physiologiquement acceptables.
  6. Utilisation d'un composé de formule I selon la revendication 1 et/ou de l'un de ses sels physiologiquement acceptables pour la préparation d'un médicament pour lutter contre les maladies.
EP92117675A 1991-10-23 1992-10-16 Thiadiazinones et médicaments les contenant, ayant en particulier une activité inotrope positive et vasodilatatrice Expired - Lifetime EP0539806B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4134893 1991-10-23
DE4134893A DE4134893A1 (de) 1991-10-23 1991-10-23 Thiadiazinone

Publications (2)

Publication Number Publication Date
EP0539806A1 EP0539806A1 (fr) 1993-05-05
EP0539806B1 true EP0539806B1 (fr) 1995-01-04

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EP92117675A Expired - Lifetime EP0539806B1 (fr) 1991-10-23 1992-10-16 Thiadiazinones et médicaments les contenant, ayant en particulier une activité inotrope positive et vasodilatatrice

Country Status (16)

Country Link
US (1) US5276027A (fr)
EP (1) EP0539806B1 (fr)
JP (1) JP3193789B2 (fr)
AT (1) ATE116644T1 (fr)
AU (1) AU653444B2 (fr)
CA (1) CA2081049A1 (fr)
CZ (1) CZ281377B6 (fr)
DE (2) DE4134893A1 (fr)
DK (1) DK0539806T3 (fr)
ES (1) ES2066540T3 (fr)
HU (1) HU214337B (fr)
MX (1) MX9206042A (fr)
NO (1) NO303013B1 (fr)
PL (1) PL171273B1 (fr)
TW (1) TW309518B (fr)
ZA (1) ZA928236B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW309520B (fr) * 1994-04-26 1997-07-01 Mitsubishi Chem Corp
DE19500558A1 (de) * 1995-01-11 1996-07-18 Merck Patent Gmbh 3-Alkoxycarbonyl-thiadiazinone
DE19502699A1 (de) * 1995-01-28 1996-08-01 Merck Patent Gmbh Arylalkyl-thiadiazinone
DE19533975A1 (de) * 1995-09-14 1997-03-20 Merck Patent Gmbh Arylalkyl-diazinone
DE10150517A1 (de) * 2001-10-12 2003-04-17 Merck Patent Gmbh Verwendung von Phosphodiesterase IV-Inhibitoren
CZ2004516A3 (cs) * 2001-10-31 2004-08-18 Merckápatentágmbh Inhibitor fosfodiesterázy typu @Ź jeho kombinace s jinými drogami a jeho použití
WO2005075456A1 (fr) 2004-02-04 2005-08-18 Altana Pharma Ag Derives de 2-(piperidin-4-yl)-4,5-dihydro-2h-pyridazin-3-one inhibiteurs de pde4
CN101602687A (zh) * 2008-06-13 2009-12-16 上海特化医药科技有限公司 6-硝基苯乙酮类化合物、其制备方法及用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4495185A (en) * 1981-11-12 1985-01-22 Imperial Chemical Industries, Plc 1,2,4-Triazin-3(2H) ones
AU614965B2 (en) * 1987-06-06 1991-09-19 Merck Patent Gesellschaft Mit Beschrankter Haftung Thiadiazinones
ATE180475T1 (de) * 1990-09-21 1999-06-15 Rohm & Haas Dihydropyridazinone und pyridazinone als fungizide

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Publication number Publication date
CZ281377B6 (cs) 1996-09-11
NO924098D0 (no) 1992-10-22
JPH05222017A (ja) 1993-08-31
CA2081049A1 (fr) 1993-04-24
US5276027A (en) 1994-01-04
NO303013B1 (no) 1998-05-18
DK0539806T3 (da) 1995-03-13
EP0539806A1 (fr) 1993-05-05
AU2723192A (en) 1993-04-29
HUT67938A (en) 1995-05-29
MX9206042A (es) 1993-04-01
JP3193789B2 (ja) 2001-07-30
NO924098L (no) 1993-04-26
AU653444B2 (en) 1994-09-29
TW309518B (fr) 1997-07-01
ATE116644T1 (de) 1995-01-15
ES2066540T3 (es) 1995-03-01
CZ263692A3 (en) 1993-05-12
DE4134893A1 (de) 1993-04-29
PL171273B1 (pl) 1997-03-28
PL296314A2 (en) 1993-05-04
HU214337B (hu) 1998-03-02
ZA928236B (en) 1993-05-06
DE59201148D1 (de) 1995-02-16
HU9203332D0 (en) 1992-12-28

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